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"'Hero' Proteins May Shield Other Proteins from Harm"

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Researchers at RIKEN and the University of Tokyo report the existence of a new class of proteins in and human cell extracts that may serve as shields that protect other proteins from becoming damaged and causing disease. An excess of the proteins, known as Hero proteins, was associated with a 30 percent increase in the lifespan of Drosophila, according to the study, which was published last week (March 12) in PLOS Biology.

"The discovery of Hero proteins has far-reaching implications," says Caitlin Davis, a chemist at Yale University who was not involved in the study, "and should be considered both at a basic science level in biochemistry assays and for applications as a potential stabilizer in protein-based pharmaceuticals."

Nearly 10 years ago, Shintaro Iwasaki, then a graduate student studying biochemistry at the University of Tokyo, discovered a strangely heat-resistant protein in Drosophila that seemed to help stabilize another protein, Argonaute, in the face of high temperatures that would denature most proteins. Although he didn't publish the work at the time, Iwasaki called the new type of protein a Heat-resistant obscure (Hero) protein-not because of their ability to rescue Argonaute from destruction, but because in Japan, the term "hero" means "weak or not rigid," and Hero proteins don't have stiff 3-D structures like other proteins do. But recognition of a more widespread role for Hero proteins in protecting other molecules in the cell gives the name new meaning.

"It is generally assumed that proteins are folded into three-dimensional structures, which determine their functions," says Kotaro Tsuboyama, a biochemist at the University of Tokyo and the lead author of the new study. But these 3-D structures are disrupted when the proteins are exposed to extreme conditions. When proteins are denatured, they lose the ability to function normally, and sometimes begin to aggregate, forming pathologic clumps that can lead to disease.

Hero proteins can survive these biologically challenging conditions. Heat-resistant proteins have been found in extremophiles-organisms known to live in extreme environments-but were thought to be rare in other organisms. In the new study, Tsuboyama and his team boiled lysates from Drosophila and human cell lines, identifying hundreds of Hero proteins that withstood the temperature.

The researchers selected six of these proteins and mixed them with "client" proteins-other functional proteins that on their own would be denatured by extreme conditions-before exposing them to high temperatures, drying, chemicals, and other harsh treatments. The Hero proteins prevented certain clients from losing their shape and function.

Next, the team tested the effects of Hero proteins in cellular models of two neurodegenerative disorders characterized by pathologic protein clumps: Huntington's disease and amyotrophic lateral sclerosis (ALS). When the Hero proteins were present, there was a significant reduction in protein clumping in both models.

"This is an extremely important finding as it may pave new therapeutic and preventive strategies for neurodegenerative diseases, such as Alzheimer and Parkinson diseases," Morteza Mahmoudi, who studies regenerative medicine at Michigan State University and was not involved in the research, writes in an email to The Scientist.

Lastly, the team genetically engineered Drosophila to produce an excess of Hero proteins. These flies lived up to 30 percent longer than their wildtype counterparts.

Not everyone is convinced that the Hero proteins play a major protective role. "Although they show these proteins help their proven targets remain folded/shielded etc, I don't think there's a broader application at all," Nihal Korkmaz, who designs proteins at the University of Washington Institute of Protein Design and also did not participate in the study, tells The Scientist in an email. She adds that many proteins she works with can withstand high temperatures and the researchers "don't mention at all if [Hero proteins] are found throughout the brain or in CSF [cerebrospinal fluid]," where they'd be able to protect against Huntington's or ALS.

The authors emphasized that there is a lot left to learn about the proteins. Each Hero protein seems able to protect some client proteins, but not all of them. Moreover, amino acid sequences differ considerably between Hero proteins, making it difficult to predict their functions. The researchers write in the study that they hope future studies will help them identify which clients each Hero might work with.

Whatever discoveries future work might hold, Tsuboyama says, the scientific community's reaction to the team's new study has been consistent: "Almost everyone says that Hero proteins are interesting but mysterious."
K. Tsuboyama et al., "A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation," Emma Yasinski is a Florida-based freelance reporter. Follow her on Twitter . PLOS Biol, doi: 10.1371/journal.pbio.3000632, 2020.

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"Hero" Proteins May Shield Other Proteins from Harm

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Researchers at RIKEN and the University of Tokyo report the existence of a new class of proteins in and human cell extracts that may serve as shields that protect other proteins from becoming damaged and causing disease.

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This study analyzed genome sequences of modern-day West Africans, which pointed out an extinct human relative that interbred with Homo sapiens. This opens a new path in evolutionary history in which different hominin species had diverged.

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A study points to the existence of an ancient human relative that interbred with Homo sapiens.

An analysis of the whole genome sequences of hundreds of modern-day West Africans, along with those of ancient Neanderthals and Denisovans, points to the existence of a "ghost" species that interbred with Homo sapiens before dying out, researchers at the University of California, Los Angeles, report yesterday (February 12) in Science Advances.

The finding further complicates an evolutionary history in which different hominin species diverged, only to-in some cases-meet up and swap genes with each other hundreds of thousands of years later. Modern humans have already been found to have interbred with Neanderthals and Denisovans.

In the new study, Arun Durvasula and Sriram Sankararaman analyzed the whole-genome sequences of people from four populations living in Nigeria, Sierra Leone, and the Gambia, as well as those from Neanderthal and Denisovan fossils. They found patterns in the genomes of two of the modern groups, Yoruba and Mende, that indicated some of their DNA sequences originated in a species other than those analyzed.

Whatever that species was, "They seem to have made a pretty substantial impact on the genomes of the present day individuals we studied," Sankararaman tells The Guardian. "They account for 2% to 19% of their genetic ancestry." He and Durvasula also found hints of the archaic species' genes in a population in Kenya, and in individuals of Han Chinese and northern and western European ancestry.

Sankararaman and Durvasula estimate that the ghost species split between 1 million and 360,000 years ago from the lineage that produced modern humans and Neanderthals, and that members of that species interbred with Homo sapiens sometime in the past 124,000 years.

"It's an exciting moment because these studies open a window showing us that there is much more than we thought to learn about our ancestors. But actually knowing who those ancestors were, how they interacted, and where they existed is going to take fieldwork to find their fossil and archaeological remains," John Hawks, an anthropologist at the University of Wisconsin-Madison who was not involved in the study, tells The Guardian.

The New York Times notes that one candidate for the ghost species is a hominin for which a skull was discovered in 2011 in Nigeria. But researchers have not yet succeeded in extracting and sequencing DNA from that fossil, or from others found in Africa that are thought to be from now-extinct hominins.

Shawna Williams is a senior editor at The Scientist. Email her at swilliams@the-scientist.com or follow her on Twitter .

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Remnants of Extinct Hominin Species Found in West African Genomes

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An analysis of the whole genome sequences of hundreds of modern-day West Africans, along with those of ancient Neanderthals and Denisovans, points to the existence of a "ghost" species that interbred with Homo sapiens before dying out, researchers at the University of California, Los Angeles, report yesterday (February 12) in Science Advances .

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Antoine Beclere University Hospital in Paris

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Antoine Beclere University Hospital in Paris

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A cancer patient successfully gave birth, which represents the 1st successful pregnancy from immature eggs that were frozen after they were matured.

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A 34-year-old woman has given birth thanks to a new fertility procedure that involved collecting, maturing, and freezing some of her eggs five years earlier. Although lab-based maturation of eggs has been done before, the case study, published yesterday (February 18) in Annals of Oncology, represents the first successful pregnancy from immature eggs that were frozen after they were matured.

"We didn't know whether or not the frozen eggs would survive and keep their potential to produce a pregnancy and live birth," study coauthor Michaël Grynberg, head of reproductive medicine and fertility preservation at Antoine Béclère University Hospital in Paris, where the procedure was carried out, tells The Guardian. "It was a good surprise for us."

The woman opted for a fertility preservation treatment after being diagnosed with breast cancer at 29 years old, as chemotherapy drugs can contribute to infertility.

The standard fertility intervention for women about to receive chemotherapy consists of a procedure in which doctors administer hormones to stimulate the ovaries to produce mature eggs and then remove and store those mature eggs for later use.

In this case, the use of these hormones was deemed too risky by the woman's doctors as the treatment might worsen her cancer. The patient also did not want to undergo surgery to have part of her ovarian tissue removed, frozen, and re-implanted after her cancer treatment, given the invasiveness of the procedure.

So researchers at Antoine Béclère University Hospital removed immature eggs from her ovaries, matured them in the lab over the course of a couple of days, and then froze them in liquid nitrogen by a process called vitrification, in which cells are rapidly cooled down to avoid the formation of destructive ice crystals.

Several years later, the doctors thawed seven of the eggs, fertilized the surviving six with sperm injections, and implanted the one resulting healthy embryo into the patient. Her baby boy, Jules, was born last summer.

"Getting eggs to mature successfully after removal from the ovary has been a challenge, so this is a very welcome positive step," the University of Edinburgh's Richard Anderson, who was not involved in the work, tells . "It isn't widely available, but this report shows it can work, when time is very short."

Since this patient's case, two more women being treated for cancer have had the same procedure at the hospital and are now pregnant, Grynberg tells The Guardian.

Catherine Offord is an associate editor at The Scientist. Email her at cofford@the-scientist.com.

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Baby Born from Egg that Was Matured and Frozen in the Lab

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A 34-year-old woman has given birth thanks to a new fertility procedure that involved collecting, maturing, and freezing some of her eggs five years earlier. Although lab-based maturation of eggs has been done before, the case study, published yesterday (February 18) in Annals of Oncology , represents the first successful pregnancy from immature eggs that were frozen after they were matured.

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Researchers and scientists have found out that artificial intelligence has identified a molecule that was capable of destroying antibiotic-resistant bacteria.

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Anewly designed artificial intelligence tool based on the structure of the brain has identified a molecule capable of wiping out a number of antibiotic-resistant strains of bacteria, according to a study published on February 20 in . The molecule, halicin, which had previously been investigated as a potential treatment for diabetes, demonstrated activity against Mycobacterium tuberculosis, the causative agent of tuberculosis, and several other hard-to-treat microbes.

The discovery comes at a time when novel antibiotics are becoming increasingly difficult to find, reports , and when drug-resistant bacteria are a growing global threat. The Interagency Coordination Group (IACG) on Antimicrobial Resistance convened by United Nations a few years ago released a report in 2019 estimating that drug-resistant diseases could result in 10 million deaths per year by 2050. Despite the urgency in the search for new antibiotics, a lack of financial incentives has caused pharmaceutical companies to scale back their research, according to STAT.

"I do think this platform will very directly reduce the cost involved in the discovery phase of antibiotic development," coauthor James Collins of MIT tells STAT. "With these models, one can now get after novel chemistries in a shorter period of time involving less investment."

Although earlier AI-based models required human supervision and produced inconsistent results, reports STAT, this new deep learning approach was trained on a library of more than 2,000 chemical compounds with something known about their antibacterial potency, using those data to predict function based on structure. The platform identified molecules that looked quite different from existing antibiotics, overcoming the bias that human researchers exhibit when they search for potential anti-bacterial compounds that have structures similar to existing antibiotics, according to STAT.

The team first used the deep learning model to screen a library of 6,000 molecules for those that may be effective against E. coli. The search detected halicin, which the authors tested against a number of cultured bacterial strains, finding that the molecule "displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae," the authors write in the paper. Halicin also fights C. difficile and a "pan-resistant" infection in mouse models, the team found.

In a subsequent screen of more than 107 million molecules from the ZINC15 database provided by the University of California, San Francisco, the AI tool identified eight molecules with structures distinct from known antibiotics but that might have potent anti-bacterial properties.

"The work really is remarkable," Jacob Durrant of the University of Pittsburgh, a drug design researcher who was not part of the study, tells The Guardian. "Their approach highlights the power of computer-aided drug discovery. It would be impossible to physically test over 100m compounds for antibiotic activity."

"Now we're finding leads among chemical structures that in the past we wouldn't have even hallucinated that those could be an antibiotic," says Nigam Shah, biomedical informatics researcher at Stanford University who was not involved in the study, in remarks to STAT. Shah cautions that a long and complex process would be required before this new antibiotic could be tested in humans, but says it's a step in the right direction. "It greatly expands the search space into dimensions we never knew existed."

Amy Schleunes is an intern at The Scientist. Email her at aschleunes@the-scientist.com.

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Anewly designed artificial intelligence tool based on the structure of the brain has identified a molecule capable of wiping out a number of antibiotic-resistant strains of bacteria, according to a study published on February 20 in .

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3-D printing has been used in medicine and dentistry, but now, many researchers are printing cells to form living human tissues to fully functional organs.

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For years, scientists have predicted that 3-D printing-which has been used it to make toys, homes, scientific tools and even a plastic bunny that contained a DNA code for its own replication-could one day be harnessed to print live, human body parts to mitigate a shortage of donor organs. So far, researchers also used 3-D printing in medicine and dentistry to create dental implants, prosthetics, and models for surgeons to practice on before they make cuts on a patient. But many researchers have moved beyond printing with plastics and metals-printing with cells that then form living human tissues.

No one has printed fully functional, transplantable human organs just yet, but scientists are getting closer, making pieces of tissue that can be used to test drugs and designing methods to overcome the challenges of recreating the body's complex biology.

First steps

The first 3-D printer was developed in the late 1980s. It could print small objects designed using computer-aided design (CAD) software. A design would be virtually sliced into layers only three-thousandths of a millimeter thick. Then, the printer would piece that design into the complete product.

There were two main strategies a printer might use to lay down the pattern: it could extrude a paste through a very fine tip, printing the design starting with the bottom layer and working upward with each layer being supported by the previous layers. Alternatively, it could start with a container filled with resin and use a pointed laser to solidify portions of that resin to create a solid object from the top down, which would be lifted and removed from the surrounding resin.

When it comes to printing cells and biomaterials to make replicas of body parts and organs, these same two strategies apply, but the ability to work with biological materials in this way has required input from cell biologists, engineers, developmental biologists, materials scientists, and others.

So far, scientists have printed mini organoids and microfluidics models of tissues, also known as organs on chips. Both have yielded practical and theoretical insights into the function of the human body. Some of these models are used by pharmaceutical companies to test drugs before moving on to animal studies and eventually clinical trials. One group, for example, printed cardiac cells on a chip and connected it to a bioreactor before using it to test the cardiac toxicity of a well-known cancer drug, doxorubicin. The team showed that the cells beating rate decreased dramatically after exposure to the drug.

However, scientists have yet to construct organs that truly replicate the myriad structural characteristics and functions of human tissues. "There are a number of companies who are attempting to do things like 3-D print ears," and researchers have already reported transplanting 3-D printed ears onto children who had birth defects that left their ears underdeveloped, notes Robby Bowles, a bioengineer at the University of Utah. The ear transplants are, he says, "kind of the first proof of concept of 3-D printing for medicine."

Bowles adds that researchers are still "a ways away" from printing more-complex tissues and organs that can be transplanted into living organisms. But, for many scientists, that's precisely the goal. As of February 2020, more than 112,000 people in the US are waiting for an organ transplant, according to the United Network for Organ Sharing. About 20 of them die each day.

For many years, biological engineers have tried to build 3-D scaffolds that they could seed with stem cells that would eventually differentiate and grow into the shapes of organs, but "to a large extent those techniques don't allow you to introduce kind of the organization of gradients and the patterning that is in the tissue," says Bowles. "There is no control over where the cells go in that tissue." By contrast, 3-D printing enables researchers with to very precisely direct the placement of cells-a feat that could lead to better control over organ development.

Differentiation

Ideally, 3-D printed organs would be built from cells that a patient's immune system could recognize as its own, to avoid immune rejection and the need for patients to take immunosuppressive drugs. Such organs could potentially be built from patient-specific induced pluripotent stem cells, but one challenge is getting the cells to differentiate into the subtype of mature cell that's needed to build a particular organ. "The difficulty is kind of coming together and producing complex patternings of cells and biomaterials together to produce different functions of the different tissues and organs," says Bowles.

To imitate the patterns seen in vivo, scientists print cells into hydrogels or other environments with molecular signals and gradients designed to coax the cells into organizing themselves into lifelike organs. Scientists can use 3-D printing to build these hydrogels as well. With other techniques, "the patterns achieved have typically been two-dimensional," Eben Alsberg, a bioengineer at the University of Illinois, tells The Scientist in an email. "Three-dimensional bioprinting permits much more control over signal presentation in 3D."

So far, researchers have created patches of tissue that mimic portions of certain organs but haven't managed to replicate the complexity or cell density of a full organ. But it's possible that in some patients, even a patch would be an effective treatment. At the end of 2016, a company called Organovo announced the start of a program to develop 3-D printed liver tissue for human transplants after a study showed that transplanted patches of 3-D printed liver cells successfully engrafted in a mouse model of a genetic liver disease and boosted several biomarkers that suggested an improvement in liver function.

Vasculature

Only in the past few years have researchers started to make headway with one of the biggest challenges in printing 3-D organs: creating vasculature. After the patches were engrafted into the mouse's liver in the Organovo study, blood was delivered to it by the surrounding liver tissue, but an entire organ would need to come prepared for blood flow.

"For any cells to stay alive, [the organ] needs that blood supply, so it can't just be this huge chunk of tissue," says Courtney Gegg, a senior director of tissue engineering at Prellis Biologics, which makes and sells scaffolds to support 3-D printed tissue. "That's been recognized as one of the key issues."

Mark Skylar-Scott, a bioengineer at the Wyss Institute, says that the problem has "held back tissue engineering for decades." But in 2018, Sébastian Uzel, Skylar-Scott, and a team at the Wyss Institute managed to 3-D print a tiny, beating heart ventricle complete with blood vessels. A few days after printing the tissue, Uzel says he came into the lab to find a piece of twitching tissue, which was both "very terrifying and exciting."

For any cells to stay alive, [the organ] needs that blood supply, so it can't just be this huge chunk of tissue.

-Courtney Gegg, Prellis Biologics

Instead of printing the veins in layers, the team used embedded printing-a technique in which, instead of building from the bottom of a slide upwards, material is extruded directly into a bath, or matrix. This strategy, which allows the researchers to print "free form in 3-D," says Skylar-Scott, rather having to print each layer one on top of the other to support the structure, is a more efficient way to print a vascular tree. The matrix in this case was the cellular material that made up the heart ventricle. A gelatin-like ink pushed these cells gently out of the way to create a network of channels. Once printing was finished, the combination was warmed up. This heat caused the cellular matrix to solidify, but the gelatin to liquify so it could then be rinsed out, leaving space for blood to flow through.

But that doesn't mean the problem is completely solved. The Wyss Institute team's ventricle had blood vessels, but not nearly as many as a full-sized heart. Gegg points out that to truly imitate human biology, "an individual cell will have to be within 200 microns of your nearest blood supply. . . . Everything has to be very, very close." That's far more intricate than what researchers have printed so far.

Due to hurdles with adding vasculature and many other challenges that still face 3-D-printed tissues, laboratory-built organs won't be available for transplant anytime soon. In the meantime, 3-D printing portions of tissue is helping accelerate both basic and clinical research about the human body.
Emma Yasinski is a Florida-based freelance reporter. Follow her on Twitter .

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For years, scientists have predicted that 3-D printing-which has been used it to make toys, homes, scientific tools and even a plastic bunny that contained a DNA code for its own replication-could one day be harnessed to print live, human body parts to mitigate a shortage of donor organs.

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How Ariprazole's Promise for Treating Autism Fell Short

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How Ariprazole's Promise for Treating Autism Fell Short

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Abilify was widely thought to be a safe drug approved for autistic children, but data has shown that it is not.

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Even as a toddler, Jaymes Lesovoy was violent. He hit and bit his parents, and he tore apart his and his sisters' toys. At 18 months of age, he was diagnosed with autism.

Jaymes' pediatrician suggested behavioral and speech therapy, but neither approach reined in the boy's aggression. In 2006, when Jaymes was 2, the doctor prescribed risperidone-an antipsychotic medication that had been approved earlier that year to treat irritability in autistic children aged 5 and older. A few years later, he added a second medication to the mix-the seizure drug valproic acid-although Jaymes does not have seizures.

Still, Jaymes acted out at home and at school, and continued to do so for years. When he was 10, another doctor suggested Jaymes try a different antipsychotic: aripiprazole. That drug had been approved in 2009 to treat irritability in autistic children aged 6 and older.

Jaymes' mother, Amber Lesovoy, was familiar with aripiprazole. She had taken the medication herself a year earlier for her own autism and bipolar disorder, and she had experienced an unusual side effect: trouble urinating, which disappeared after she stopped taking the drug. She worried Jaymes might also experience side effects but felt she had few choices left. "I was a teen mom," she says. "I didn't have a lot of life experience, so all I knew to do was what the professionals told me."

Jaymes was underweight when he started taking aripiprazole, but within a few weeks, he was always hungry: "He would sneak food; he would eat huge amounts at mealtimes. Any chance he got to get food, he would take it," Lesovoy says. The pounds started to pile on.

There were other, more disturbing changes. When he started with aripiprazole, his mother says, he began to flail his arms, kick his legs, and scrunch up his face without warning-severe involuntary muscle spasms called tardive dyskinesia. (Jaymes was later diagnosed with Tourette syndrome, which his doctors say explains the leg-kicking.) After a year on the drug, Jaymes had gained 50 pounds. He had fewer angry outbursts, but Lesovoy decided the side effects were not worth it. Of all the drugs Jaymes had been prescribed, aripiprazole was "one of the worst," she says.

It has been 11 years since the U.S. Food and Drug Administration (FDA) approved aripiprazole for children with autism. The drug, marketed as Abilify, initially had a reputation of having fewer side effects than risperidone, its only competitor in this population. But a decade's worth of data suggest that is untrue. As with many antipsychotic medications, long-term use of aripiprazole can lead to tardive dyskinesia, as it did for Jaymes. It might also be linked to heart problems in autistic children. And perhaps most concerning, aripiprazole appears to cause just as much weight gain as risperidone, compounding a problem many children with autism already have.

"The weight gain is not subtle," says Eric London, director of autism treatment research at the New York State Institute for Basic Research in Developmental Disabilities. He says he has discontinued the drug's use in 15 to 20 percent of the autistic people he treats, one or two of whom have gained more than 100 pounds.

A string of lawsuits over the past several years have charged that aripiprazole's developers, the pharmaceutical companies Otsuka Pharmaceutical and Bristol-Myers Squibb, did not adequately warn users of the drug's potential side effects-including compulsive behaviors such as gambling, sex addiction and excessive shopping. Other lawsuits alleged that the companies marketed the drug illegally for conditions it may not help. Most doctors interviewed for this story were aware of the risks. One described aripiprazole as a "last resort" in his treatment arsenal-a drug intended only for children who harm themselves or others. Still, a few say they consider aripiprazole a cure-all that can ease minor behavioral problems such as general agitation. Many clinicians say they prescribe the drug for a year or longer. Unlike risperidone, though, aripiprazole has not been shown to work long term in children with autism. Neither Otsuka nor Bristol-Myers Squibb responded to repeated requests from Spectrum for comment.

From 2014 to 2016, more than 500,000 children were prescribed aripiprazole in the United States. And among children with autism, the number taking antipsychotic medications overall is about one in six, according to one 2016 study. "That is concerning and suggests possible over-prescription or overuse," says Matthew Siegel, director of the Developmental Disorders Inpatient Research Collaborative at Spring Harbor Hospital in Westbrook, Maine. "Those are our most powerful, potentially most problematic drugs. Should that really be the most common [type of] drug we use?

High hopes:

Aripiprazole was discovered decades before it was approved for use in children with autism. Scientists at Otsuka Pharmaceutical, based in Tokyo, Japan, started work on the compound in the late 1970s and teamed up with Bristol-Myers Squibb more than a decade later to develop it into pill form. In 2002, the two big companies together brought that pill to market under the brand name Abilify, originally branding it as a novel antipsychotic to treat schizophrenia.

Many doctors say they had high hopes for the drug at first-in part because it purported to work differently from all of its predecessors. Whereas other atypical antipsychotics, including risperidone, inhibit the neurotransmitter dopamine, aripiprazole blocks dopamine only some of the time (the exact mechanism is unknown). For that reason, the drug was expected to cause fewer side effects than risperidone. Because it also acts on the neurotransmitter serotonin, from 2004 to 2016 the FDA signed off on its use for a laundry list of other conditions tied to either dopamine or serotonin, including bipolar disorder, depression, and Tourette syndrome.

The agency approved risperidone for autistic children in 2006, and soon after, Bristol-Myers Squibb and Otsuka started testing aripiprazole for that same use. In a 2009 study of 218 children with autism, they found that those who took the drug for eight weeks significantly improved on a standard test of irritability compared with controls. A second 2009 study in 98 children reinforced those results. Both studies hinted that children treated with aripiprazole may gain weight and have severe muscle tremors, but they concluded that the drug is safe and well tolerated overall.

Based on those trials, in 2009 the FDA approved aripiprazole to treat irritability in autistic children. Some researchers say they remember that soon after, drug representatives were touting aripiprazole as safer and at least as effective as risperidone. "When the sales reps came or when [aripiprazole] was presented, it was presented as, you know, 'It's an effective drug but has less weight gain compared to risperidone,'" says Antonio Hardan, professor of psychiatry and behavioral sciences at Stanford University in California. He says he does not remember specific interactions with drug representatives but recalls discussing the new approval with his colleagues. "People were excited about it," he says.

Sales of aripiprazole skyrocketed. In 2013, it was the highest grossing medication in the U.S. But it also drew lawsuits from thousands of people over side effects. The companies also faced lawsuits over how they marketed the drug. According to charges brought by the U.S. Department of Justice, drug representatives had visited doctors' offices to promote aripiprazole's use in children before the FDA had approved it for that use. Otsuka and Bristol-Myers Squibb both denied any wrongdoing, but both agreed to settlements: In 2007, Bristol-Myers Squibb agreed to pay $515 million to the U.S. Department of Justice, and Otsuka agreed to pay the department more than $4 million a year later. Bristol-Myers Squibb also settled a 2016 suit for $19.5 million that alleged it had marketed the drug for off-label use-that is, for conditions the drug was not approved to treat. In 2016, the FDA compelled Otsuka and Bristol-Myers Squibb to update the drug's warning labels.

According to Michael Oldani, a medical anthropologist at Concordia University in Mequon, Wisconsin, the companies' aggressive marketing helped to expand aripiprazole's use to conditions such as autism. By merely conducting studies to extend the drug's use to children, its makers also became eligible under FDA rules to extend the life of their patent for at least six months from the original expiration date of October 2014. That extension allowed the companies to retain exclusive rights to the drug-and to continue pricing it at about $800 a month for a typical dose. By contrast, generic versions of the drug now available run to about $15 a month.

The companies overplayed the drug's safety from the outset, Oldani says. He worked as a drug representative for Pfizer from 1989 to 1998. He also served as an expert witness in a 2013 case against Bristol-Myers Squibb related to Abilify's off-label promotion and side effects. "The big thing for me is always side effects," Oldani says. "The mythology with [aripiprazole prescriptions] is they were super-duper safe."

Risky reactions:

At least one thing has become clear after a decade of aripiprazole's use: The drug's effects can vary dramatically between people. That's something Vida Penikas, who has three autistic children, learned firsthand.

When Penikas' son J. was a toddler, he rarely spoke and was obsessed with anything that could spin. He was diagnosed with autism around age 5. He did well in school and was reasonably happy until he entered middle school, his mother says, when he spiraled into a dark depression. ( Spectrum is using the boys' first initials to protect their privacy.)

Penikas brought J. to their nurse practitioner. It was 2008, the year before aripiprazole was approved for autistic children, but the nurse practitioner recommended the drug "right off the bat," Penikas says. "He said they've seen that Abilify works well with autistic kids." Almost immediately, J. calmed down. His depression lifted and his outbursts waned. The drug worked so well that J. took aripiprazole until he turned 21 three years ago and no longer seemed to need it.

We think in true clinical practice over long-term treatment that we cannot differentiate weight gain between [the two drugs].

J.'s younger brother T. had an entirely different experience. He was diagnosed with autism after he started school, and by the time he was 9, he was having intense anxiety attacks. At first, the doctor prescribed several drugs that did little to ease the boy's anxiety. Based on J.'s experience, Penikas thought aripiprazole might help and suggested it.

It turned out to be a nightmare, she says. Within months, T. became newly obsessed with random objects-at first Tic Tac candies, then duct tape. Soon after, he became aggressive, the opposite of the drug's intended effect. One day about 10 weeks after he started taking aripiprazole, T. put a kitchen knife to his neck and threatened to stab himself if Penikas kept him from attending a friend's sleepover. Penikas called 911, and T. was admitted to a psychiatric hospital, where doctors decided to wean him off aripiprazole. When he stopped taking the drug, his aggression waned.

"I would say [aripiprazole] works pretty well for a lot of people," says Sarah Cheyette, a pediatric neurologist at Sutter Health in San Carlos, California. But there are notable exceptions, she says. Without research to identify who the likely responders are, clinicians have relied largely on their own judgement about when and to whom to prescribe aripiprazole. Some say they prescribe risperidone for children who are hyperactive, compulsive or have erratic sleep patterns, and turn to aripiprazole if a child has a family history of obesity or diabetes, presuming it is associated with less weight gain.

But a growing body of research is beginning to suggest aripiprazole and risperidone may not be as different as doctors have assumed when it comes to side effects. One 2016 analysis of 11 randomized controlled studies of aripiprazole and risperidone found that they are about equally effective. That same year, a head-to-head comparison of the drugs found that weight gain from each is "uncannily similar," says Craig Erickson, associate professor of psychiatry at the Cincinnati Children's Hospital in Ohio, who led the study.

Prior to that study, "myself and others would go around the country . . . and we'd say, 'Hey, we think there's less weight gain [with aripiprazole].' But then we really came around to this understanding," Erickson says. "We think in true clinical practice over long-term treatment that we cannot differentiate weight gain between [the two drugs]." Similarly, although physicians have widely used aripiprazole to address self-injury, the drug may work best for children whose aggression comes from autistic meltdowns, according to a reanalysis of the original results.

Erickson says two trials he was involved in at around the same time as the original clinical trials in children might yield additional insight. But results from those trials are not fully available. Data from one of the studies appear on the government's trial registry, but the results are "not in a level of detail that scientists in the field expect or can fully utilize," he says. The other study has no public results; the lead investigators of both studies did not respond to multiple requests for comment.

One outstanding question about aripiprazole is how well it works in the long term. Otsuka completed a small study in 2014, the results of which suggested the drug has limited value past 28 weeks of use; the FDA then required the drug's makers to add this detail to its label. But many researchers say the study was too small for them to draw conclusions about the drug's usefulness over a long period. The study also hinted that girls fare worse on aripiprazole than do boys, although the reasons for these differences are unclear. Many researchers say these findings in particular warrant further study.

Source: IQVIA National Sales Perspectives. Graphic by Krista Fuentes.

Emerging concerns:

In 2017, the FDA tasked an independent advisory committee-comprising pediatricians from a range of specialties-with reviewing aripiprazole's side effects in children.

The committee examined a report the FDA had prepared earlier that year highlighting 78 serious cases of adverse events, based on data from the agency's national drug surveillance program. According to the report, 14 children, including one with autism, had died-5 of them by suicide. The drug's label warns that aripiprazole is associated with "suicidal thoughts and behaviors," but the FDA report concluded that aripiprazole could not directly be linked to any of the deaths.

The report also concluded that no new safety warnings were warranted. In half of the non-fatal cases, the drug had stopped being effective. For the other half, the report said, "there were no clear patterns or trends for a new safety signal."

The committee's conclusions after reviewing the report, however, were less reassuring. The members expressed concern about weight gain associated with aripiprazole, and other adverse reactions that can be related to weight gain, such as stroke and heart problems, neither of which appears on the drug's label for use in children. The FDA's surveillance data, for instance, included five cases of stroke. One 10-year-old boy had developed coronary artery stenosis, a condition normally seen in adults.

"I understand the child had underlying congenital heart disease, but congenital heart disease at 10 years old does not cause coronary artery stenosis or ischemic cardiomyopathy. That, to me, was like, really?" committee member and pediatrician Christy Turer said during a meeting in Rockville, Maryland, in 2017, according to the meeting's minutes.

When you are in the clinic, you have people with real problems. You can't just throw your hands up and say, 'Go home.'

Turer argued that the heart problems, stroke and metabolic issues were all "new safety events" worthy of new warning labels and further study. Another member agreed with her, but the remaining 12 did not. Turer requested that the FDA follow up on her concerns over cardiovascular side effects, but she says she never heard back from agency officials. "[They are] not held to doing that or communicating back to us if they looked into it," she says.

In response to questions about these concerns, an FDA spokesperson told Spectrum that the agency had decided not to pursue any inquiry into an association between aripiprazole and an increased risk of cardiovascular problems in children. "We did not receive any follow-up information on the cases that provided additional information suggesting that aripiprazole caused the events," the spokesperson said.

Despite these concerns, some clinicians say that having aripiprazole as an option is better than nothing-at least until research suggests otherwise. "When you are in the clinic, you have people with real problems," London says. "You can't just throw your hands up and say, 'Go home, I have nothing to do for you because the studies don't work.'"

Amber Lesovoy, though, has a different perspective: She says doing nothing would have been better than using aripiprazole. She still blames the drug for Jaymes' "unnecessary suffering."

Jaymes is now 16. He has continued to gain weight, and he has become increasingly violent. His family moved him to a group home about an hour away from their house. But he acts up when he is at the home-about a year ago, for example, he became angry and tried to swallow his hearing aid. Still, it is the safest option for Jaymes and the rest of the family, Lesovoy says.

"Medication is a necessary evil for Jaymes, and I understand that," she says. "But I really regret certain ones, and Abilify is one of the ones I really regret."

This article was original published February 19 on Spectrum, the leading site for autism research news.

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How Aripiprazole's Promise for Treating Autism Fell Short

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Even as a toddler, Jaymes Lesovoy was violent. He hit and bit his parents, and he tore apart his and his sisters' toys. At 18 months of age, he was diagnosed with autism. Jaymes' pediatrician suggested behavioral and speech therapy, but neither approach reined in the boy's aggression.

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Scientists Use Online Game to Research COVID-19 Treatment

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Scientists Use Online Game to Research COVID-19 Treatment

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As scientists play a game called Foldit, it helps researchers to further design and identify proteins that may be able to neutralize SARS-CoV-2 proteins.

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Institute of Laboratory Animal Services at the Chinese Academy of Medical Sciences

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Institute of Laboratory Animal Services at the Chinese Academy of Medical Sciences

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Throughout this research, monkeys have been found to develop protective antibodies to SARS-CoV-2, which supports the idea of using plasma from recovered patients to develop a treatment for COVID-19.

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Whether people develop immunity to SARS-CoV-2 after being infected once is a pressing question for policymakers, public health professionals, and everyone affected by the spreading COVID-19 pandemic. It's of particular interest to several research groups and companies currently developing plasma therapies, whereby antibody-containing blood plasma is extracted from recovered patients and administered to patients with severe cases to help them fight off the infection.

Now, a study in monkeys provides some clues. Three rhesus macaques did not develop a second infection after recovering from a first exposure to the coronavirus and being reexposed to SARS-CoV-2, suggesting that primates are capable of developing at least some short-term immunity to the pathogen. The research, posted as a preprint to March 14, has yet to undergo peer review. To the authors, the results indicate that reports of some COVID-19 survivors being "re-infected" a second time can be explained by issues with testing rather than a failure to develop immunity.

"This is a really critical preliminary study," says Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill who wasn't involved in the study. Although many questions remain as to how the human immune system responds to the virus, "it's the start of an answer that's going to be really important to all of us."

Based on these results, the team questions the reports of COVID-19 survivors recovering and being discharged upon testing negative for the virus, only to then develop another infection.

The team's research began while the outbreak was mostly restricted to China. Around early February, reports surfaced that recovered COVID-19 patients who were discharged from hospitals later tested positive again, explains Chuan Qin, an experimental pathologist at the Institute of Laboratory Animal Sciences at the Chinese Academy of Medical Sciences. Qin and his colleagues, some of whom have previously studied monkey responses to MERS, wanted to investigate whether it was possible to become re-infected with the new coronavirus.

The team applied a dose of SARS-CoV-2 into the windpipes of four adult rhesus macaques. The researchers detected high concentrations of the virus in the animals' noses and throats, which peaked three days after the initial infection. This was accompanied by reduced appetite, weight loss, and an increased breathing rate. After sacrificing one of the monkeys and performing a necropsy a week after the initial exposure, the team found the animal had traces of the virus across many body tissues and had developed interstitial pneumonia-characterized by an inflammation of the lungs' alveoli, which is one of the key symptoms of COVID-19 that can occur in people.

The team collected the blood sera of the three other animals to track whether they were developing antibodies to the virus. Using a specialized assay, they found the monkeys' blood contained antibodies that targeted the spike protein of SARS-CoV-2, a surface protein the virus uses to enter human cells. Antibody levels were relatively low during the first week after infection, but surged at three and four weeks. "Our study found that neutralizing antibodies are produced in the process of recovery after SARS-CoV-2 infection," Qin writes in an email to The Scientist.

Roughly a month days after the initial exposure to SARS-CoV-2, the researchers verified that the animals had cleared the infection. They couldn't detect the virus from swabbing the nose, throat, or anus, and there were no strikingly unusual features in the lungs based on a chest X-ray.

The team then exposed two of the remaining monkeys to a second dose of the coronavirus. Although the animals developed a slight fever, neither showed weight loss. In addition, the researchers couldn't detect the virus based on nose, throat, or anal swabs. One of the two animals was euthanized and necropsied, which confirmed that there was no viral replication across body tissues.

Support for plasma therapy for COVID-19

The researchers conclude that "neutralizing antibodies produced by SARS-CoV-2-infected monkeys can protect animals from reinfection," Qin explains. Based on these results, the team questions the reports of COVID-19 survivors recovering and being discharged upon testing negative for the virus, only to then develop another infection. They suspect that this is probably the result of false-negative PCR tests in the hospital that missed lingering virus, and they note in the study that diagnostic techniques need to be further refined.

Columbia University virologist Angela Rasmussen agrees with this interpretation. "This study suggests that reinfection is likely not occurring frequently, if at all. It indicates that infection results in protective immunity against SARS-CoV, at least in the short term," she writes in an email to The Scientist. Virologists on Twitter concur that reinfection with SARS-CoV-2 is unlikely, citing other recent preprints that describe a production of antibodies in people infected with SARS-CoV-2019.

It's unclear how long this protective immunity lasts. Sheena Cruickshank, an immunologist at the University of Manchester, points out that the study is very short in duration. It's too soon to say whether the researchers' observations are due to the immediate, initial antibody response to the virus or to a long-lasting immune memory.

Typically, viral infection triggers plasma B cells to produce antibodies, but, eventually, memory B cells, which survive for long periods of time, are also stimulated to differentiate into plasma B-cells that generate more-targeted and more-effective antibodies upon re-encountering the same pathogen. It's not clear whether the antibody surge the team observed is part of the "stage when [initial] antibody levels are still dropping off, rather than a true memory response," Cruickshank writes to The Scientist in an email. In addition, the study only followed the immune responses of two macaques. "These are really tiny numbers to infer anything," she adds.

Lengthier studies that follow animals or people at least three months after infection are critical to understanding long-term immune responses to SARS-CoV-2, she explains. Research on other coronaviruses suggest different long-term immune responses. For instance, studies in SARS patients find that antibody levels fade after a few years. Some cold-causing coronaviruses "tend to induce immunity that is very short-lived, at around three months," notes Peter Openshaw, a professor of experimental medicine at Imperial College London, in a recent statement in response to recent discussions on herd immunity in the UK. (Last week, British officials seemingly presented a plan to combat the outbreak that was communicated as allowing the deadly virus to spread to build immunity among the general population and thereby slow transmission-an approach decried by many scientists. UK Health Secretary Matt Hancock later insisted to the , "herd immunity is not our policy. It's not our goal.")

Despite the small numbers of animals observed in the study, "in these circumstances, this study is still informative and useful," Rasmussen says. To her, the results underscore the possibility that plasma therapy approaches could be a useful treatment option. Administering antibodies from other people is thought to be one way to provide patients with immediate immunity. Some studies suggest this approach reduced the risk of death for flu patients during the 1918 influenza pandemic and improved the prognosis for certain SARS patients in the 2003 outbreak in Hong Kong. Several studies testing such therapies for COVID-19 are currently underway. "Convalescent plasma in particular is a therapy that could be undertaken fairly rapidly and might be a good therapeutic intervention until we can develop an effective vaccine," Rasmussen says.

To Gralinski, the study underscores that non-human primates could be a useful animal model to study COVID-19, because their symptoms are similar to-but not exactly the same as-those in humans. "These animals certainly aren't progressing to acute respiratory distress syndrome or anything like that, [which] you see in some people," she says. Nevertheless, the animals may prove useful in studying whether vaccines, drugs, antivirals, and other therapies may be promising in people, she says.

"We've only known about this virus for ten, eleven weeks right now," Gralinski says. "It's great to see any type of data this quickly."
L. Bao et al., "Reinfection could not occur in SARS-CoV-2 infected rhesus macaques," Katarina Zimmer is a New York-based freelance journalist. Find her on Twitter Correction (March 18): A previous version of this article incorrectly stated that upon viral infection, plasma B cells produce antibodies on the spot. The article has been updated to reflect the fact that they take longer to generate. @katarinazimmer. bioRxiv, doi:10.1101/2020.03.13.990226, 2020.

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Monkeys Develop Protective Antibodies to SARS-CoV-2

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Whether people develop immunity to SARS-CoV-2 after being infected once is a pressing question for policymakers, public health professionals, and everyone affected by the spreading COVID-19 pandemic. It's of particular interest to several research groups and companies currently developing plasma therapies, whereby antibody-containing blood plasma is extracted from recovered patients and administered to patients with severe cases to help them fight off the infection.

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Mite-destroying gut bacterium might help save vulnerable honey bees

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Mite-destroying gut bacterium might help save vulnerable honey bees

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This research helped pave a way to combatting Colony Collapse Disorder (CCD).

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Genetically altering symbiotic gut bacteria in honey bees is successful at killing varroa mites, which tend to make bees sick and leave them at an increased risk of colony collapse disorder, according to a study published today (January 31) in Science.

Colony collapse disorder (CCD) occurs when the majority of a hive abandons ship, leaving behind the queen, honey and pollen stores, and young, immature bees behind. Without the workforce of a full hive, the colony fails. According to the US Department of Agriculture, there does not appear to be a single cause of CCD, rather, it is likely a combination of disease, parasites, poor nutrition, pesticide exposure, and other stressors on the hive.

One possible contributor to unhealthy hives are Varroa destructor mites, an invasive species that arrived in North America in the early 1980s. Not only do these parasites feed...

To fight back against Varroa, researchers looked to Snodgrassella alvi, a symbiotic bacterium found within the gut of honey bees. Genetic modification of the microbes enabled them to destroy the mites from the inside out through RNA interference (RNAi). The engineered bacteria produced double-stranded RNA that induced the mites to launch an RNAi defense to destroy those sequences. Because the bacterial sequences matched those from the varroa genome critical to the mites' survival, the silencing mechanism wiped out the mite transcripts as well, killing the parasites

"It is a bit like a customized medicine for honey bees," Jeffrey Scott, an insect toxicologist at Cornell University who was not involved with the study, tells Science. "Being able to engineer a gut microbe and specifically regulate gene expression in the host has enormous implications."

By using S. alvi as a manufacturer, the team was able to provide a continued supply of the RNA, providing a useful window for the bees to fight back against the mites. The effects lasted for the duration of the 15-day-long experiment and bees with the altered bacteria were 70 percent more likely to kill mites within 10 days than those without it.

"If the technique works in the field, that could be the end of Varroa and the viruses," Robert Paxton, a bee ecologist at Martin Luther University who was not involved with the study, tells Science.

While the results of this small-scale experiment are encouraging, the method won't be used in the wild anytime soon. Releasing bacteria with gene-silencing potential invariably raises containment questions along with concerns that mutations may cause unintended consequences.

"You're turning off genes [via RNAi]," honeybee epidemiologist Dennis vanEngelsdorp of the University of Maryland who was not involved with the study tells Science News. "There has to be a very healthy debate about 'how do we regulate this?'"

Lisa Winter is the social media editor for The Scientist. Email her at lwinter@the-scientist.com or connect on Twitter @Lisa831.

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Engineered Microbe in Bees' Guts Fends off Deadly Varroa Mite

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Genetically altering symbiotic gut bacteria in honey bees is successful at killing varroa mites, which tend to make bees sick and leave them at an increased risk of colony collapse disorder, according to a study published today (January 31) in Science .

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Cutting-edge CRISPR gene editing appears safe in three cancer patients

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Cutting-edge CRISPR gene editing appears safe in three cancer patients

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CRISPR edits DNA and T-cell therapy in order for the immune system to kill tumors, which have been found successful in 3 patients. This launches a new chapter in the cancer immunotherapy field.

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Launching a new chapter in the fast-moving cancer immunotherapy field, scientists have blended two cutting-edge approaches: CRISPR, which edits DNA, and T cell therapy, in which sentries of the immune system are exploited to destroy tumors. Two women and one man, all in their 60s-one with sarcoma and two with the blood cancer multiple myeloma- received CRISPR-altered versions of their own cells last year, researchers report online in Science this week.

For these pioneers, the benefits were limited: One has since died, and the disease has worsened in the others. But the clinical trial, which underwent years of regulatory scrutiny, wasn't designed to try to cure cancer, says Carl June, a cancer researcher at the University of Pennsylvania (UPenn) who co-led the work. Rather, its goal was to show that the strategy appeared feasible and safe.

By that measure, scientists agree, it succeeded. "This is a Rubicon that has been decisively crossed," says Fyodor Urnov, a genome editor at the University of California (UC), Berkeley. The study, he says, the first of its kind in the United States, answers "questions that have frankly haunted the field."

The researchers used CRISPR alongside another strategy that incorporates new DNA into immune cells. June's team helped pioneer that strategy in 2010, when it added DNA to T cells from three men with chronic leukemia and returned those cells to the patients. The results were remarkable: Two men are still alive and healthy today. Others were testing the same approach, called CAR-T cell therapy-after the inserted chimeric antigen receptor gene that helps the infused T cells latch onto and destroy cancer cells with a specific protein on their surface. Two CAR-T cell therapies are now approved for patients with leukemia and lymphoma.

But with time, the therapy's limitations have come into focus. Not every cancer patient is helped, and even those who are can suffer a relapse, says Edward Stadtmauer, who treats blood cancers at UPenn and co-led the new study. And solid tumors like those in the brain and pancreas have proved tough to treat.

Using CRISPR to knock out selected genes while also adding DNA, it was hoped, might make T cells even more powerful and persistent. But CRISPR brought its own uncertainties. Lab studies have revealed "off-target" effects, in which unintended DNA gets modified. No one knew whether T cells with sliced and diced genes could even survive in the human body. Last year, Vertex Pharmaceuticals and CRISPR Therapeutics announced that two patients treated for inherited blood diseases with CRISPR-edited cells were doing well. But details were sparse.

June, Stadtmauer, and their colleagues began by hunting for patients whose tumors produced a protein called NY-ESO-1, a target for the gene the researchers would add to their T cells. The patients also needed to carry a specific version of human leukocyte antigen, an immune gene complex that could help the infused T cells flourish. The four patients who qualified were all extremely ill, as is the norm for such a novel therapy. A woman with multiple myeloma had undergone three bone marrow transplants. Another, in her late 30s with sarcoma, became too sick to treat while her cells were being prepped in the lab, a process that takes 4 to 6 weeks. She entered hospice care and died.

To try to rev up the patients' T cells against their disease, the scientists used CRISPR to knock out two genes that encode what's known as the T cell receptor. The group also crippled a third gene, for a protein called PD-1. PD-1 puts the brakes on immune responses, and eliminating its effects, June's team theorized, might enrich the T cells' powers. Then, they inserted the gene for a different T cell receptor that would target NY-ESO-1.

Intensive monitoring of the patients, including blood draws to study their altered T cells, confirmed that CRISPR had left some off-target changes. But they were few, and the number of cells with these unintended DNA changes faded over time. Encouragingly, the CRISPR-edited cells persisted at least 9 months-versus about 2 months in comparable CAR-T cell therapy studies. Imaging showed "beautiful, healthy T cells," June says, that in lab studies beat back cancer months after they'd been infused.

But in patients, outcomes were modest. The best response was in the sarcoma patient, whose primary tumor shrank, though his cancer later progressed. "It wasn't like you turned off those genes and those T cells started doing things that were amazing," says Antoni Ribas, an oncologist at UC Los Angeles. Ribas, June, and others offer potential reasons, including the small number of patients treated, possible limitations of NY-ESO-1 as a target-selected in part for its safety record-and the failure to knock out all three genes in many of the cells.

Some of the authors are working with companies to commercialize the method. But much experimentation lies ahead. "This whole area is just teeming with different ideas," Stadtmauer says. A handful of other trials, including several in China, are offering CRISPR-modified cells to patients with cancer or other diseases. A company called PACT Pharma, which Ribas helped found, is running a trial that uses CRISPR to target gene mutations within solid tumors.

What June's group offers is "a needed start" for giving patients CRISPR-edited T cells, Ribas says. From now on, he adds, "It's going to be easier-because they did it first."

doi:10.1126/science.abb1990

More from News

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Cutting-edge CRISPR gene editing appears safe in three cancer patients

# data[].attributes.attachment_link.description
Launching a new chapter in the fast-moving cancer immunotherapy field, scientists have blended two cutting-edge approaches: CRISPR, which edits DNA, and T cell therapy, in which sentries of the immune system are exploited to destroy tumors.

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Doctors in London are trying to disarm body's defenders in order to seek for a new treatment that can be used for people with blockages in their coronary arteries.

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Seeking a new treatment for people who have dangerous blockages in their coronary arteries, doctors in London are trying to disarm the body's own defenders. The 90 patients in the study receive the usual treatments for heart disease, such as small tubes called stents to prop open their narrowed arteries. But half of the patients in the phase II trial, conducted by clinical pharmacologist Albert Ferro of King's College London and colleagues, also pop pills targeting a class of immune cells called neutrophils. Researchers think that by invading the fatty obstructions, or plaques, in clogged arteries, neutrophils make them even more dangerous. The drug is designed to steer the cells away.

Interfering with neutrophils is an audacious idea. Neutrophils make up some 70% of the white cells in blood, with billions spawned every day by stem cells nestled in the bone marrow. The cells patrol the bloodstream and wage war on pathogens, and their defensive role is so vital that people who lose their neutrophils in the course of cancer treatment can die from infections.

But their scorched-earth tactics are tough on the body. "They are the classic double-edged sword," says immunologist Michael Fessler of the U.S. National Institute of Environmental Health Sciences. For example, the enzyme neutrophil elastase, which neutrophils release to kill invading bacteria, also erodes the extracellular matrix, the mesh of proteins and sugars that cradles cells and provides structural support for tissue.

Neutrophils can also malfunction. In some conditions, such as chronic obstructive pulmonary disease (COPD), they seem to lose their sense of direction: Instead of homing in on bacteria, they wander. Researchers suspect these vagrant neutrophils release neutrophil elastase and other molecules at the wrong spots, including the lungs, causing the tissue damage seen in COPD. And as people age, neutrophils become less effective at combating infections and more harmful to the body.

"We are now beginning to understand that neutrophils are linked to many diseases that blight our population," says pulmonologist Elizabeth Sapey of the University of Birmingham in the United Kingdom. With that realization has come optimism that these cells aren't off-limits for medical interventions. Researchers have been cautious about targeting neutrophils, fearing that doing so would leave patients at the mercy of pathogens. "The age-old idea was that you couldn't touch neutrophils," Sapey says. But a series of clinical trials has offered reassurance that it can be safe to restrain the cells.

Although some of those trials yielded mediocre results, researchers have pressed on-and their persistence may be paying off. Two clinical trials with neutrophil-focused drug candidates reported encouraging findings last year; one could lead to the approval of the first medication targeting these immune cells, in a rare autoimmune condition. The trial Ferro and his colleagues are conducting, the first to attempt to stem cardiovascular disease by interfering with neutrophils, is expected to have results by 2021 or 2022. And a burst of new findings about the cells' diversity and behavior is likely to inspire new ways to manipulate them. "There is real hope in this field," Sapey says.

Neutrophils flock to the site of an injury or infection, wherever it occurs. The cells navigate to trouble spots with the help of receptors on their surface, such as one known as CXCR2, which detects a trail of alarm molecules released by damaged tissue. If the cells happen upon microbes, they launch a multipronged attack, gobbling the pathogens, spilling corrosive chemicals, and sometimes launching webs of DNA, known as neutrophil extracellular traps (NETs), that snag and kill the invaders. Hematopoietic stem cell transplants given to some cancer patients to replace their bone marrow underscore the importance of these defenses. "If the graft doesn't take, you will have no neutrophils, and that is not survivable," says immunologist Klaus Ley of the La Jolla Institute for Immunology.

Yet studies over the past 2 decades have darkened their image. The cells in effect "drop atomic bombs" in the body, says immunologist Paul Kubes of the University of Calgary. Neutrophil elastase and other chemicals they discharge may drive inflammation and damage to the airways in cystic fibrosis and intractable cases of asthma. NETs, for their part, can provoke the immune system to attack a patient's own cells in the autoimmune disease lupus, and they spur formation of blood clots in the potentially lethal condition deep-vein thrombosis. NETs can also worsen arterial plaques by promoting inflammation, cell biologist Venizelos Papayannopoulos of the Francis Crick Institute in London and colleagues found in 2015. Neutrophils can even abet cancer, spurring growth of new blood vessels that feed tumors and helping the abnormal cells spread to other parts of the body.

More than 10 years ago, such disease links prompted some companies to begin to develop compounds that inhibit neutrophil elastase. Others tried to restore neutrophils' navigational abilities, which are faulty in COPD and other conditions, by blocking the protein PI3K, an enzyme involved in controlling cell movement.

Neutrophils are linked to many diseases that blight our population.

Elizabeth Sapey, University of Birmingham

More than a dozen clinical trials scrutinized these potential drugs in many conditions. The good news is that the compounds didn't cripple defenses against infections. But most of the trials found minimal benefits. As a result, several big pharmaceutical companies have given up. In 2019, GlaxoSmithKline jettisoned danirixin and nemiralisib, the two neutrophil-targeting drug candidates it had been developing for lung diseases. Merck and AstraZeneca have also recently abandoned once-promising compounds.

But researchers say there's still hope, arguing they haven't yet pinned down what doses to use, how best to deliver potential drugs, and which aspects of neutrophil biology to target. In trials for COPD and other lung disorders, Sapey notes, patients inhaled the compounds. But because most neutrophils ply the bloodstream, inhaled drugs may not reach faulty cells, she says. Nervous about side effects, investigators may also have kept doses too low.

Hematologist and oncologist Steven Pavletic of the U.S. National Cancer Institute and his colleagues think they can do better. In a phase I safety trial, Pavletic and his team have started to give larger amounts of the neutrophil elastase inhibitor alvelestat to patients with the lung condition bronchiolitis obliterans. The ailment strikes a significant percentage of people who receive hematopoietic stem cell transplants during cancer treatment, developing when immune cells from the transplant attack the recipient's own tissue. Neutrophils swarm into the lungs and may encourage scar tissue to build up in the bronchioles, the lungs' smallest airways, which can cause them to clog. For transplant recipients, bronchiolitis obliterans is like having an unstoppable asthma attack, Pavletic says.

He adds that alvelestat probably won't reverse bronchiolitis obliterans, but by blocking neutrophil elastase, it could stop the disease from getting worse. "Even a marginal improvement could lead to a major improvement in lung function."

Researchers are further along in evaluating a way to target neutrophils to treat a rare autoimmune disease in which the immune system produces antibodies against its own neutrophils-a condition known as antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. The antibodies glom onto the cells, which then get stuck in small blood vessels and release their chemical load, leading to inflammation that can cause kidney damage and other problems. In the first year after diagnosis, patients with the disease are nine times more likely to die than people in the general population, and current treatments, which include steroids and immune-suppressing drugs, are one reason for this high mortality, notes nephrologist David Jayne of the University of Cambridge.

In a recent trial involving 331 ANCA vasculitis patients, Jayne and colleagues tested the experimental drug avacopan, which stymies C5a, a protein in the blood that helps spur neutrophils to release their inflammation-promoting contents. The results of the phase III trial, announced late last year, revealed that the drug was about 20% more likely to produce remissions after 1 year than steroids were. It improved patients' kidney function and was also less harmful than steroids. Jayne predicts avacopan will be approved by the U.S. Food and Drug Administration and "will be a complete replacement for steroids" in treatment of ANCA vasculitis.

Although many efforts to target neutrophils aim to inhibit them, Sapey and her colleagues believe rejuvenating neutrophils could help boost immune function in older people. An existing drug, the cholesterol-lowering medication simvastatin, may do the job, they found. Simvastatin had caught their attention because some evidence suggested people taking it for high cholesterol are less vulnerable to infections. When the team members exposed neutrophils to simvastatin in the lab, they found it boosts the cells' migration accuracy and improves their performance in other ways. And in a phase II trial of the drug in 62 older people with bacterial pneumonia and sepsis, Sapey and her colleagues determined that adding simvastatin to the normal treatment regimen reduced the severity of infections and allowed the patients to spend more time out of the hospital over the next year.

"That was highly unexpected and very exciting," says Sapey, whose team reported the findings last year in the American Journal of Respiratory and Critical Care Medicine. They are now planning a larger study of the drug, and she says it might also work against other common bacterial problems in the elderly, such as urinary tract and skin infections.

The therapeutic possibilities are likely to broaden as researchers learn more about the biology of neutrophils. The cells have traditionally been seen as the immune system's cannon fodder-simple, expendable killers. But neutrophils, it turns out, aren't so simple after all. "They are not merely the cells that clear microbes from infected sites," Papayannopoulos says.

"The most exciting thing is that the cells are much more heterogeneous than we thought," says immunologist Leo Koenderman of University Medical Center Utrecht in the Netherlands. With techniques such as single-cell RNA sequencing, researchers have discovered that neutrophils come in multiple varieties. And their properties can vary by time of day. In humans, the cells are much more aggressive toward pathogens at night than during daylight hours, and they crank up different genes depending on the hour.

This diversity enables the cells to specialize and take on more tasks than researchers expected. Some neutrophils have moved up the chain of command and help control the activity of other immune cells. For example, they can either spur T cells to attack pathogens or rein them in. The cells can also take on alternative roles when they enter damaged tissue. If they encounter microbes, they become fighters. But if an injury is not infected, they become healers. Chemicals they release can stimulate new blood vessels to form and spark the production of replacement cells.

Blunting the attack

Ongoing clinical trials aim to treat a range of diseases by targeting proteins that abet tissue damage by neutrophils. Earlier tests had reassured researchers that the strategy would not leave patients defenseless against infections.

Intravital microscopy, which reveals the movements of cells within the body, suggests the lives of these immune cells are eventful. Researchers long assumed that once neutrophils left the bloodstream and moved into infected or injured tissues, they would eventually self-destruct, allowing the inflammation at the site to clear. But several microscopy studies have revealed more complex migrations. In a 2011 study, for example, Anna Huttenlocher of the University of Wisconsin, Madison, and colleagues tracked neutrophils in zebrafish that had wounds on their fins. The scientists found that individual neutrophils moved into and out of a wound several times before eventually departing for good.

Now, Ferro and his colleagues are trying to interrupt one leg of the neutrophils' journey. In patients with heart disease, the cells worm into the fatty plaques lining the coronary arteries. There, they release chemicals, including neutrophil elastase, that may make these plaques more likely to fracture and spawn blood clots, which can trigger heart attacks.

The drug candidate that Ferro and colleagues are testing in people with serious plaques, AZD5069, blocks CXCR2, the receptor that helps neutrophils navigate to infected and inflamed locations. In animal tests, the compound deters neutrophils from entering sites of inflammation.

Death rates from cardiovascular diseases have been dropping for decades in many countries thanks to lifestyle changes, such as a decline in smoking, as well as drugs that lower cholesterol and combat blood clotting. But heart disease still kills more than 600,000 people in the United States every year. "There's clearly a big gap that remains in therapy for these patients," Ferro says. Within a couple of years, he hopes to know whether deflecting neutrophils can help.

Some researchers remain skeptical that the current crop of experimental neutrophil-targeting drugs will work outside certain rare diseases. The cells have multiple redundant pathways that control their activity, Koenderman notes. A neutrophil "is extremely robust," he says. The idea that a single drug could correct its misbehavior "is pretty naïve," he says.

However, researchers are already developing new approaches, including DNA-destroying enzymes that might slice up NETs and prevent blood clots. And as scientists dig deeper into the cells' biology, they may find new ways to keep these immune soldiers in check, Fessler says. "There is hope that with increasing understanding of neutrophils, we will have more sophisticated approaches down the line."

doi:10.1126/science.abb5095

Mitch Leslie writes about cell biology and immunology.

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New drugs aim to disarm the immune system's 'atomic bomb' cells

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Seeking a new treatment for people who have dangerous blockages in their coronary arteries, doctors in London are trying to disarm the body's own defenders. The 90 patients in the study receive the usual treatments for heart disease, such as small tubes called stents to prop open their narrowed arteries.

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Next generation water splitter could help renewables power the globe

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Next generation water splitter could help renewables power the globe

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Renewable energies could now use electrolyzers that split water into oxygen and hydrogen gas, which can bolster the use of renewable energy around the world.

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Running the world on renewable energy is simple, in principle: Harvest solar and wind energy, and use any extra to power devices called electrolyzers that split water into oxygen (O ₂) and hydrogen gas. Hydrogen (H ₂) can serve as a fuel; it is also a staple of the chemical industry. The trouble is that current electrolyzers are costly, requiring either expensive catalysts or pricey metal housings. Now, researchers report combining the best of both approaches to make a version that needs only cheap materials.

"I consider this a great breakthrough," says Hui Xu, a chemical engineer at Giner Inc., an electrochemistry company. Xu says he and his colleagues presented similar results at a Department of Energy meeting last year, but have not yet published them. Their work and another team's new device, described this week in Nature Energy, could bolster the global embrace of renewable energy if the new electrolyzers prove to be cheap and stable during many years of operation. "We are on the cusp of getting that done," says Yushan Yan, a chemical engineer at the University of Delaware, Newark, who is working on similar technology. A handful of small companies, including one he founded, have formed to commercialize it.

Scientists have known how to split water into H ₂ and O ₂ for more than 200 years: Put two metal electrodes in a jar of water, apply an electrical voltage between them, and H ₂ and O ₂ will bubble up at separate electrodes. Because a mix of the gases can explode, today's most common setups separate the anode and cathode with a thick, porous plastic sheet. They also use metal catalysts-most often inexpensive ones such as nickel and iron-to speed the reactions.

To make the water able to better conduct ions that move through the devices, today's most common electrolyzers add high levels of potassium hydroxide (KOH) to the water. At the cathode, or negative electrode, water molecules split into H⁺ and OH- ions. The H⁺ ions combine with electrons from the cathode to make H ₂. The OH- ions diffuse through the membrane to the anode, or positive electrode, where they react to generate O ₂ and water.

But KOH is highly caustic, so engineers have to build their devices out of expensive inert metals such as titanium, says Yu Seung Kim, a chemist at Los Alamos National Laboratory. That drawback prompted researchers in the 1960s to develop a version of the technology known as a proton-exchange membrane (PEM) electrolyzer, in which the dividing membrane is designed to selectively allow H⁺ ions through. A PEM cell's catalysts aren't on the electrodes themselves, but are tethered to opposite sides of the membrane. In this setup, catalysts on the anode side split water molecules into H⁺ and OH- ions, with the latter instantly reacting at the catalysts to form O ₂ molecules. The H⁺ ions then migrate through the plastic membrane to the cathode side, where catalysts tethered to the membrane turn the H⁺ ions into H ₂.

Because OH- ions don't migrate through PEM cells, there's no need for highly alkaline conditions. The devices also typically produce hydrogen at five times the rate of the alkaline version. But these membrane cells have their own downsides: They still need some expensive corrosion-resistant metals to withstand acidic conditions produced by the proton-conducting membrane. They also require catalysts made from platinum and iridium. Those metals are expensive and rare. For example, the global production of iridium is only 7 tons. "There is simply not enough [precious metals] for large-scale hydrogen production," Xu says.

Now, Kim and his colleagues at Los Alamos, along with researchers at Washington State University, say they've combined the best of both approaches. Their new device creates a highly alkaline environment to encourage water splitting. But it does so with the PEM approach of tethering catalysts to opposite faces of an ion-conducting membrane. As with the KOH setup, catalysts on the cathode side split water molecules into H⁺ and OH- ions. The former converts to H ₂, and the latter travels through the membrane, known as an anion exchange membrane (AEM). It is designed to create a highly alkaline local environment that speeds the travel of OH- ions to the anode side, where tethered catalysts prompt them to react to make O ₂.

The upshot is that alkaline conditions near the membrane allow the electrolyzer to rely on cheap and abundant nickel-, iron-, and molybdenum-based catalysts to split water. Yet, because the alkalinity is localized, the electrolyzer can be built from stainless steel. The new device generates hydrogen about three times faster than conventional alkaline devices, though still more slowly than commercial PEM electrolyzers, Kim and his colleagues report. "The combination of the older alkaline technology and membrane PEM technology is the path forward," Xu says.

The new setup needs to prove its durability. Initial indications suggest the membrane begins to break down after only about 10 hours of operation. Kim says the main problem is likely that the polymer membrane readily absorbs water. Over time, this may cause the catalyst particles to come unglued and drift away. The team hopes that adding fluorine to the membrane will repel the water. With that and other fixes, Kim hopes, AEM electrolyzers could join solar cells and windmills as a key technology for a carbon-free world.

doi:10.1126/science.abb6714

Bob is a news reporter for Science in Portland, Oregon, covering chemistry, materials science, and energy stories.

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Next generation water splitter could help renewables power the globe

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Running the world on renewable energy is simple, in principle: Harvest solar and wind energy, and use any extra to power devices called electrolyzers that split water into oxygen (O 2) and hydrogen gas. Hydrogen (H 2) can serve as a fuel; it is also a staple of the chemical industry.

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"Did an experimental drug help a U.S. corona-virus patient?"

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On 26 February, what seems like ages ago in the ongoing pandemic, the University of California Davis Medical Center in Sacramento finally got RNA test results confirming that a critically ill patient it had been treating for a week had coronavirus disease 2019 (COVID-19). (It took 4 days before the U.S. Centers for Disease Control and Prevention agreed to evaluate the patient samples because the person did not meet the strict criteria the agency then had in place, and 3 more days for the result to come back.) The patient, who for privacy reasons UC Davis physicans refer to only as they but who has been described as a woman by California's governor and state health officials, was the first likely case of U.S. community spread detected, meaning that the source of her infection was not known: She had had not traveled outside the United States to an infected area or been in known contact with a confirmed case.

The difficulty the medical center faced acquiring a test for its patient received widespread media scrutiny, but her fate largely escaped notice: After her condition declined, the UC Davis doctors secured what's known as compassionate use permission from the Food and Drug Administration to test an experimental drug on their patient outside of a clinical trial. The drug, remdesivir made by Gilead Sciences, is given by an intravenous drip. Several randomized, placebo controlled trials of remdesivir for COV-19 are now underway in China and the United States and everyone is looking for quick hints on whether the drug works-a new preprint out today on the drug's use in three COVID-19 patients is raising questions about its ultimate value.

Remdesivir cripples an enzyme called RNA polymerase that is used by many viruses to copy themselves; it does not specifically target SARS-CoV-2, the virus that causes COVID-19. But it worked well in test tube and animal studies of human coronaviruses, cousins of SARS-CoV-2 called severe acute respiratory syndrome and Middle East respiratory syndrome, that cause similar respiratory conditions. (Ebola also is an RNA virus, but a test of remdesivir in the Democratic Republic of the Congo last year showed that it didn't work for that disease.)

George Thompson, an infectious disease specialist at the medical center, was on the team that cared for the California patient and spoke to ScienceInsider about the case. This interview has been edited for clarity and length; additional information added by Science Insider is in brackets.
Q: When did the patient start on remdesivir?
A: From diagnosis to therapy, about 36 hours, which is very short for emergency approval of an investigational drug.
Q: How sick was the patient?
A: We thought they were going to pass away.
Q: Did you do extracorporeal machine oxygenation (ECMO)? [This is a type of artificial lung that removes blood, pumps oxygen into it, and then returns it back to the body. It has been used extensively in China to save some critically ill COVID-19 patients.]
A: We had started those conversations to see how we would do it logistically, and they were very close to needing it, but their health started to turn around. We have some severe influenza cases every year that end up on ECMO, but nobody likes to do it. Those patients are so sick and they require a lot of time, a lot of resources. But we do it if we need to. And we were willing to do it for that patient.
Q: One truism of antivirals for acute diseases is that if you start them late, they don't work. Do you think that the point at which you gave her the treatment was early enough for it to have worked?
A: I think so. One requirement was that the patient had to have a positive test [showing the presence of SARS-CoV-2] right before starting the drug to make sure that they hadn't spontaneously already cleared the virus. The day after the infusion of the drug, they consistently got better. I can't prove it's related. I wish we had been able to do serial [polymerase chain reaction] PCR testing of their blood, but we couldn't because of lack of resources. With most investigational drugs tested in, say, macaque monkeys, there's a nice correlation between the administration of the drug and a drop in the amount of virus in the blood. That's what we hoped we could have seen in this patient.

[PCR can amplify a tiny amount of viral RNA so that it can be detected and is the basis of most SARS-CoV-2 tests.]
Q: What do you mean by a lack of resources?
A: The county only had 20 coronavirus tests for the whole county. That patient already had a confirmed infection and was not a priority for using them.
Q: Couldn't you take serial blood samples, store them, and look at them later?
A: We have all those samples saved in our local hospital and we're going to be able to do the testing next week from what I've been told. We finally have our own home-brewed [SARS-CoV-2] test up and running and I think that'll tell more of the story. If the drops in their viral loads are temporally related to remdesivir, it's a much more compelling argument than, They lived, so it must have worked. But then again, I've heard stories that many COVID-19 patients just have the virus in their respiratory samples and not their blood.
Q: When would you expect to see that drop in viral load if it was due to remdesivir?
A: Within the first 24 hours you really want to see a [big drop]. But I think we've got a lot to learn about this disease.
Q: Has the patient been discharged?
A: To protect privacy, let's just say they are doing well.
Q: Have you treated other patients at UC Davis Medical Center who have confirmed COVID-19?
A: Yes, but they had moderate disease and it was mild enough for them to go home. None would have qualified for compassionate use of remdesivir, which is only given to patients with severe disease.
Q: That's a conundrum though because remdesivir has the best chance of working in patients who are treated early, before the disease becomes severe.
A: For most any infectious disease, I think the earlier we start drugs the better. But it's a risk versus benefit question. What if this drug causes liver toxicity in 50% of the people, and we've given it to somebody who was probably going to do well without it?

[Clinical trials underway will look at all stages of disease.]
Q: Are you planning to test other experimental drugs for COVID-19?
A: We've already been contacted by a whole bunch of companies with different compounds. So, I think we'll be able to offer most anybody with confirmed COVID-19 some experimental protocol in a clinical trial. There's a lot of interest in chloroquine, and interferon with Kaletra.

[Chloroquine is an antimalarial, interferon is an immune system messenger, and Kaletra is a combination of two protease inhibitors used to treat HIV infection.]
Q: Was what you saw frightening?
A: Well, it can be severe. My research lab works on a pathogen, Coccidioidomycosis fungus, that must be studied in a BSL-3 [biosafety level 3] lab. So I'm pretty used to wearing all the gear. [BSL-3 is the second strictest level of containment.] There's a lot of fear in the hospital. Nurses need to talk a lot about it. And respiratory therapists want to talk a lot about what are you going to do for a patient who's on a nebulizer [a machine that turns liquid medicines into a mist].
Q: Many people talk about this disease with great authority based on reports they've read. My sense of this virus is it's really nasty for people who are older than 80, and for people who have heart conditions, diabetes, hypertension, but for most healthy people, it's going to be like a flu. It typically doesn't do much of anything to kids. Is that your perception of this having seen the disease?
A: That's my general perception based on the literature and what we know of the virology, but it's pretty early, right? We've had such poor testing capacity, I don't think we really have clinical experience with the breadth of the disease. Our first couple of patients have been, middle-age, healthy people. But again, you know, if you have some very minor version of it, you're probably not going to seek any care. So that side of the iceberg-I just don't think we'd have clinical experience with yet.
*Correction, 13 March: Due to a transcription error, an earlier version of this story said Thompson studies coxsackievirus.Thompson's references to the patient have been changed to they/their, his original language.

doi:10.1126/science.abb7243

Jon is a staff writer for Science.

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Did an experimental drug help a U.S. coronavirus patient?

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On 26 February, what seems like ages ago in the ongoing pandemic, the University of California Davis Medical Center in Sacramento finally got RNA test results confirming that a critically ill patient it had been treating for a week had coronavirus disease 2019 (COVID-19). (It took 4 days before the U.S.

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Newly discovered 'magic methyl' reaction could turbocharge the potency of some drugs

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Newly discovered 'magic methyl' reaction could turbocharge the potency of some drugs

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This "dream reaction" could help in drug discovery as doctors may be able to give patients less of a drug with more safety and reduced side effects.

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For years, drug discovery chemists have struggled to streamline a process that can boost a drug's potency up to 2000-fold: "magic methylation." The reaction sweeps out single hydrogen atoms and replaces them with methyl groups-reshaping the drug molecule to more easily interact with its biological targets. But carrying out this sleight of hand is so difficult that few researchers even try. Now, a team of chemists reports it has created a new catalyst that performs this delicate exchange with ease on a wide variety of druglike molecules, an advance that could lead to novel treatments for everything from cancer to infectious diseases.

"This paper is just stunning," says Tim Cernak, an organic chemist at the University of Michigan, Ann Arbor, who was not involved in the research. The new catalyst manages the reaction in one easy step-a huge improvement on previous multistep methods that were expensive and time-consuming. "This is the wish [of] every drug hunter," Cernak says. "It really is a dream reaction."

To understand the dream, it helps to know one way chemists build drug molecules, explains M. Christina White, an organic chemist at the University of Illinois, Urbana-Champaign. Most drug molecules contain a skeleton of carbon atoms shaped as a rod or a ring, with multiple hydrogen atoms hanging off each carbon. Chemists act as molecular surgeons, cutting out specific carbon or hydrogen atoms and replacing them with oxygen or nitrogen atoms. If researchers want to add a magic methyl group (which consists of one carbon atom bonded to three hydrogen atoms), they often have to start over, building a new skeleton from scratch.

White wanted to find a way to add a methyl group at the end of the drug building process. To do that, she needed to surgically snip one carbon-hydrogen (C-H) bond at a time, without cleaving the other dozen or more C-H bonds in the molecule. Adding further difficulty, C-H bonds are among the strongest in organic molecules, which makes it harder to target just one bond without affecting others, White says.

Nature builds and reshapes molecules "in a totally different way," White says. Chemical changes are made using large, complex enzymes that grasp hydrocarbon scaffolds so that just one C-H bond nuzzles up to the enzyme's catalytic site-the point at which a reaction takes place. However, each enzyme typically works with only one specific molecule. "If I want to work on a different molecule, I need a new enzyme," White says. "We want [a reagent that is] just as selective, but general."

In an effort to find just such a catalyst, White and then-graduate student Mark Chen in 2007 devised a snowflake-shaped compound with an iron atom at its center that added oxygen atoms to desired spots in druglike molecules. The catalyst could work as selectively as an enzyme. But it simply didn't work on a lot of molecular structures or when it was next to a nitrogen atom, which are common in drug molecules.

But White's team kept at it. In 2015, she and her colleagues devised a set of conditions that allowed the iron catalyst and a variant to add oxygen atoms to druglike molecules. And in 2019, they created a similar manganese-based catalyst that performed the oxygen-for-hydrogen swap on druglike molecules containing nitrogen and other common add-ons.

But that was just the first step. Now, White's team reports it has come up with chemical additives that help this latest catalyst complete the "magic methyl" process. After replacing a hydrogen with an oxygen, it steals a methyl group from a reagent known as trimethylaluminum and inserts it in oxygen's place. White's team carried out this molecular surgery on 41 different hydrocarbons, including 16 common druglike scaffolds, the researchers report today in Nature.

The upshot, White says, is that this reagent will now make it simple and cheap for drug hunters to insert "magic methyl" groups into their molecules. "We hope a lot more drugs with the magic methyl effect will be discovered," White says.

This could help "across the board" in drug discovery, says David Rees, chief scientific officer of Astex Pharmaceuticals. Where adding a methyl group does increase a drug's potency, doctors may be able to give their patients less of a drug. That could improve safety and reduce side effects. Among the drugmakers he knows, Rees says, "Everyone will jump on this."

doi:10.1126/science.abb7567

Bob is a news reporter for Science in Portland, Oregon, covering chemistry, materials science, and energy stories.

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Newly discovered 'magic methyl' reaction could turbocharge the potency of some drugs

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For years, drug discovery chemists have struggled to streamline a process that can boost a drug's potency up to 2000-fold: "magic methylation." The reaction sweeps out single hydrogen atoms and replaces them with methyl groups-reshaping the drug molecule to more easily interact with its biological targets.

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Hiroyuki Imachi's sub found microbes from an ancient lineage of Archaea that would help further investigate life's greatest leaps towards complexity.

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Cramped in a small submarine 2,500 meters below the Pacific's surface in 2006, microbiologist Hiroyuki Imachi scanned the ocean floor for signs of microbial life.

As the sub drifted over the bottom of Japan's Nankai Trough - a hotbed of understudied microbes living off methane bubbling up from tectonic faults - Imachi spotted a nest of small clams against a whitish microbial mat, suggestive of an active methane seep below. The submersible's robotic arm plunged a 25-centimeter tube into the blackish-gray sediment to retrieve a core of muck.

It would take another 12 years of lab work for Imachi and colleagues to isolate a prize they hadn't even set out to find - a single-celled microbe from an ancient lineage of Archaea, a domain of life superficially similar to bacteria. That find could help biologists reconstruct one of life's greatest leaps toward complexity, from simple bacteria-like organisms to more complicated eukaryotes, the enormous group of chromosome-carrying creatures that includes humans, platypuses, fungi and many others.

"Patience is very important in doing successful science," says Imachi, of the Japan Agency for Marine-Earth Science and Technology in Yokosuka. He and his colleagues published their findings in the Jan. 23 Nature, to enthusiastic acclaim from fellow microbiologists. "I'm very lucky."

JAMSTEC (CC-BY-NC)

Many scientists think an unusual meal kicked off the evolution of more complicated cells about 2 billion years ago. An ancient archaean, the theory goes, gobbled up a bacterium that, instead of being dinner, sparked a symbiotic relationship in a process called endosymbiosis ( SN: 6/8/74). Eventually, the bacterium evolved into mitochondria, the energy-producing cellular structures that fueled the rise of complex life.

Living remnants of ancient archaeal lineages persist in some of Earth's most extreme environments, and scientists are exploring these microbial hot spots for clues about the ancestor of all eukaryotes. One such environment is the deep-sea floor. Despite making up about 65 percent of Earth's surface, biologists have only a faint picture of the microbial multitudes that thrive there. Genetic sequencing of dredged up mud has given biologists one way of studying these communities of bacteria and archaea uniquely adapted to the cold, oxygen-less deep. But genes can reveal only so much.

So scientists seek to grow cultures of microbes in the lab to study what these organisms look like and how they behave. But extreme microbes present unique challenges. Simply plating these organisms on a petri dish, providing nutrients and waiting for growth hadn't ever worked - possibly because scientists weren't effectively re-creating the microbes' extreme environment, says Masaru Nobu, a microbiologist at the National Institute of Advanced Industrial Science and Technology in Tsukuba, Japan, who joined Imachi's project after it started.

So Imachi, Nobu and their colleagues tried to re-create a methane seep in the lab, drawing inspiration from a bioreactor used to treat municipal sewage. The team pumped methane gas into a meter-tall cylindrical chamber, kept at 10° Celsius and stacked with polyurethane sponges that mimic porous deep-sea sediment. A slow, steady flow of artificial seawater kept the sponges saturated.

The team then watered down a clump of mud from the Nankai Trough sediment core, sopped up the slurry with the sponges, stacked them in the reactor - and waited.

"There was a lot of nervousness," Nobu says of that time in December 2006. "We didn't know if we'd get what we wanted."

M.K. Nobu and H. Imachi

Each year, the researchers sequenced genes of microbes in the sponges. After a volatile first couple of years, the microbial community began to stabilize and grow. "Most of the organisms that were active in the reactor were organisms that were actually active in the natural environment," Nobu says. With a stable community of thousands, if not tens of thousands, of different kinds of microbes to draw on, the team could try to pick out and grow individual strains.

Samples from the reactor were placed into 200 glass bottles, each filled with a different energy source and cocktail of antibiotics to weed out bacteria and allow different archaea to grow.

The team had its first eureka moment in 2012, detecting an archaean new to science that they called MK-D1 in very low numbers amid numerous bacterial strains in one bottle. But each time the team tried to isolate the archaean in a new bottle, the microbe just wouldn't grow. Months of trial and error followed. "It was really frustrating," Nobu says.

Then, the researchers had an idea: Perhaps the microbe was actually growing, but at a slow pace, a result of its deep-sea home. "It's very cold down there, there's not a lot of energy," Nobu says.

So the team measured growth with a more sensitive technique, called quantitative PCR, that can quantify abundance from whiffs of DNA. Sure enough, MK-D1 was there and growing, just more slowly than any other single-celled microbe ever cultured. E. coli, for instance, can replicate itself in about 20 minutes. MK-D1 takes two to three weeks to divide.

"No microbe we knew about grew this slowly," Nobu says. "Understanding this was a revelation."

Meanwhile, another archaea discovery in 2015 rocked the world of microbial ecology. A new group dubbed Asgard archaea had been discovered from genetic material dredged up from a hydrothermal vent in the Arctic Ocean. Asgards have many eukaryotic genes, leading some scientists to argue that Asgards are the closest living relatives of ancient archaea that may have given rise to all complex life on Earth ( SN: 12/15/15).

Imachi and Nobu were stunned when DNA evidence confirmed that they'd unwittingly spent the last nine years cultivating their own Asgard, MK-D1. If it could be isolated, Imachi's team would be the first to actually glimpse a living member of this exciting but mysterious group.

The researchers finally got a stable culture of MK-D1 to thrive - with a bacterial partner that it needs to survive - and in 2018, took their first look under a microscope. The neat, tiny spheres seen at first seemed unlikely to be the sort of thing that may have begotten complexity. But over months, the microbes grew odd, tentacle-like protrusions. Imachi "initially thought the sample had been contaminated," he says. But the observation was sound, prompting the researchers to propose a model for how these tentacles might have ensnared other microbes - a probable first step in endosymbiosis.

The team gave MK-D1 a proper name, Prometheoarchaeum syntrophicum, after the Greek god Prometheus who, the myths say, introduced fire to humanity. Much remains to be learned about P. syntrophicum and what, if anything, it can tell us about our origins. In the meantime, Imachi is still sifting through the microbes in his reactor.

As he puts it, "uncultured microbes are waiting."

Questions or comments on this article? E-mail us at feedback@sciencenews.org

Editor's Note:

This story was updated on February 24, 2020, to correct that the researchers detected MK-D1 in 2012, not 2011.

A version of this article appears in the March 14, 2020 issue of Science News.

Jonathan Lambert is the staff writer for biological sciences, covering everything from the origin of species to microbial ecology. He has a master's degree in evolutionary biology from Cornell University.

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Microbiologists took 12 years to grow a microbe tied to complex life's origins

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Cramped in a small submarine 2,500 meters below the Pacific's surface in 2006, microbiologist Hiroyuki Imachi scanned the ocean floor for signs of microbial life. As the sub drifted over the bottom of Japan's Nankai Trough - a hotbed of understudied microbes living off methane bubbling up from tectonic faults - Imachi spotted a nest of small clams against a whitish microbial mat, suggestive of an active methane seep below.

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"Turning human bodies into compost works, a small trial suggests"

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Very Large Telescope, Antofagasta, Chile

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Very Large Telescope, Antofagasta, Chile

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Very Large Telescope, Antofagasta, Chile

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David Enrenreich and his team used this telescope to analyze and examine planet WASP 76b, and their findings resulted in that this planet can produce "iron rain".

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On one distant world, "heavy metal" could be a weather forecast. Telescope observations indicate that an exoplanet nearly 400 light-years away has iron rain.

The planet, dubbed WASP 76b, is an extreme kind of exoplanet known as an ultrahot gas giant ( SN: 7/30/19). These worlds "are complete oddballs," says astronomer David Ehrenreich of the University of Geneva. They get blasted with so much radiation from their suns that their dayside temperatures rival some stars ( SN: 6/5/17). Meanwhile, the nightsides of ultrahot gas giants tend to be much milder.

Until now, no one has gotten a close enough look at an ultrahot gas giant to see how such stark temperature contrasts affect atmospheric chemistry across the planet. Ehrenreich's team used the Very Large Telescope in Chile to examine starlight filtering through WASP 76b's atmosphere as the exoplanet passed in front of its sun during two orbits in 2018. Those observations revealed the chemical components of different regions of the atmosphere.

While the atmosphere showed traces of iron gas where the planet was transitioning toward nighttime, no iron was detected at the transition from night to day, researchers report online March 11 in Nature. This suggests that, as gaseous iron on WASP 76b's dayside swirls toward the nightside - which is almost 1,000 degrees Celsius cooler - the iron condenses into liquid raindrops. Because those raindrops fall deep into the atmosphere overnight, astronomers don't see iron in the atmospheric gas as it moves from night to day.

"It's a giant gaseous planet, so there's no ground" to get covered in iron puddles, Ehrenreich says. Instead, the researchers suspect that iron raindrops eventually reach depths so hot that they vaporize back into iron gas.

Questions or comments on this article? E-mail us at feedback@sciencenews.org

Maria Temming is the staff reporter for physical sciences, covering everything from chemistry to computer science and cosmology. She has bachelor's degrees in physics and English, and a master's in science writing.

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Heavy metal may rain from the skies of planet WASP 76b

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On one distant world, "heavy metal" could be a weather forecast. Telescope observations indicate that an exoplanet nearly 400 light-years away has iron rain. The planet, dubbed WASP 76b, is an extreme kind of exoplanet known as an ultrahot gas giant ( SN: 7/30/19).

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The fossil, 'Wonderchicken', was discovered by Daniel Field and his team, which is significant as it is the first fossil to have survived from the end-Cretaceous extinction.

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Behold the Wonderchicken, the earliest modern bird ever found.

Asteriornis maastrichtensis lived 66.7 million years ago, less than a million years before the asteroid impact that doomed all nonavian dinosaurs. The winged and beaked descendants of this quail-sized bird, however, survived that mass extinction event, forming a long lineage that includes modern chickens and ducks.

Based on analyses of fossil remains, which consist of a nearly complete skull and a few limb bones, the bird is closely related to the most recent common ancestor of land fowl and waterfowl, researchers report March 18 in Nature.

A. maastrichtensis ' skull is "a never previously seen mashup of ducklike and chickenlike features," says Daniel Field, a vertebrate paleontologist at the University of Cambridge. "It's like a turducken."

Previous estimates, based on molecular analyses of living bird groups, suggest that modern birds evolved before the mass extinction event roughly 66 million years ago. But this is the first fossil to definitively place a modern ancestor on the scene. The age of the fossil, in fact, suggests that those previous estimates, ranging from 139 million to 89 million years ago, might have overestimated how early these birds arose, Kevin Padian, a vertebrate paleontologist at the University of California, Berkeley, writes in a commentary in the same issue of Nature.

Modern-type birds share several key traits, such as toothless beaks and fused foot bones. The almost 11,000 living bird species - the paleognaths (flightless birds such as ostriches), anseriformes (waterfowl), galliformes (land fowl) and neoaves (the remaining 95 percent of living bird species) - all share a common ancestor, Field says. "We think that ancestor lived at some time before the end of the Age of Dinosaurs," he says. But there are very few bird fossils surviving from before the asteroid impact.

Phillip Krzeminski

The new fossils were discovered in Belgium, in a small rock about the size of a digital camera battery. The rock, made of hardened marine sediments, looked like nothing special from the outside, Field says, just "a few broken bird limb bones poking out." But any bird bones dating to just before the mass extinction event were intriguing enough that he wanted a closer look.

So Field and his colleagues used computed tomography, a kind of X-ray scanning, to peer inside the rock. And that's when they saw the skull. The team knew right away they had something special. "The timeline was: See the skull, scream 'Holy shit,' give my Ph.D. student a high five, and then start calling it the Wonderchicken."

The front part of the skull is chickenlike, including the nasal bone that formed part of the nostril, helping to shape its beak. "A barnyard chicken will eat anything you put in front of it," Field says, and that's reflected in the chicken's nonspecialized beak shape. That's in contrast to other birds, which have beaks clearly specialized for their particular diets - think the tearing bill of a raptor or the long slender sipping beak of a hummingbird.

That beak shape suggests that, like chickens, the ancient bird was also not a picky eater. And that may have been a crucial trait, Field says. "An unspecialized diet is the kind of feature that might have helped animals like the Wonderchicken survive" after the asteroid impact.

But part of the skull is more characteristic of waterfowl like ducks. Those features include a distinctive bone that projects from the back of the skull out to the base of the eye socket and a hooked bone at the back of the jaw. Analyses of the limb bones, meanwhile, suggest that A. maastrichtensis had fairly long legs. The rock containing the fossils consists of marine sediments, suggesting that the bird was a shorebird.

D.J. Field/Univ. of Cambridge

"This is one of the most important bird fossils that has been found in quite some time," says Stephen Brusatte, a vertebrate paleontologist at the University of Edinburgh, who was not involved in the study. "It raises the intriguing possibility that small size and a shoreline habitat may have helped these birds survive the end-Cretaceous extinction" when so many other, larger dinosaurs did not.

Questions or comments on this article? E-mail us at feedback@sciencenews.org

Carolyn Gramling is the earth & climate writer. She has bachelor's degrees in geology and European history and a Ph.D. in marine geochemistry from MIT and the Woods Hole Oceanographic Institution.

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'Wonderchicken' is the earliest known modern bird at nearly 67 million years old

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Behold the Wonderchicken, the earliest modern bird ever found. Asteriornis maastrichtensis lived 66.7 million years ago, less than a million years before the asteroid impact that doomed all nonavian dinosaurs. The winged and beaked descendants of this quail-sized bird, however, survived that mass extinction event, forming a long lineage that includes modern chickens and ducks.

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Legos take about 100 to 1,300 years to break down!

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Legos take about 100 to 1,300 years to break down!

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Andrew Turner and his team have been using X-ray fluorescence spectrometers in order to measure the chemical composition of Legos washed up in the water.

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If you've ever had the misfortune of stepping on a Lego, you know the plastic building blocks have absolutely no give. Now, scientists have discovered another unpleasant consequence of the toys' indestructibility: A single Lego could take hundreds of years to break down in the ocean.

Earth's oceans are littered with plastic of all kinds ( SN: 11/13/19). But estimating how long that trash takes to disintegrate in seawater is often a challenge, because it's difficult to date fragments of debris with unknown origin. But it's fairly easy to identify a piece of Lego by its distinct shape, says Andrew Turner, an environmental scientist at the University of Plymouth in England. And because the chemical additives used to make Legos have changed over time, the composition of each brick contains clues about when it was made.

Turner and colleagues used an X-ray fluorescence spectrometer to measure the chemical compositions of washed-up Lego blocks, which had been collected by beach cleanup volunteers in Cornwall, England, since 2010. Using the blocks' chemical fingerprints, the team identified bricks manufactured around the 1970s. One key chemical indicator was cadmium, used to make bright yellow and red pigments from the early 1970s until the early 1980s, when it was phased out due to toxicity.

The researchers assume the beached Legos were lost to sea around the time of their purchase. To gauge how worn down the beached Legos got during 30 to 40 years at sea - due to factors like abrasive sediment and exposure to sunlight - the researchers used their X-ray fluorescence measurements to match weathered Legos with pristine versions of the same bricks kept in collections since the 1970s.

Across 14 pairs of matching Legos, the weathered versions had 3 to 40 percent less mass than their mint-condition counterparts. Based on those measurements, it would take an estimated 100 to 1,300 years to completely break down a single Lego brick, researchers report in the July 2020 Environmental Pollution.

Prior research has shown that plastic water bottles take decades to break down in the ocean. But since many plastic components used to make electronics and other consumer products are closer in thickness and sturdiness to Lego bricks than water bottles, Turner suspects the several-hundred-year timescale may be more representative of plastic degradation overall in seawater.

Questions or comments on this article? E-mail us at feedback@sciencenews.org

Maria Temming is the staff reporter for physical sciences, covering everything from chemistry to computer science and cosmology. She has bachelor's degrees in physics and English, and a master's in science writing.

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Legos may take hundreds of years to break down in the ocean

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If you've ever had the misfortune of stepping on a Lego, you know the plastic building blocks have absolutely no give. Now, scientists have discovered another unpleasant consequence of the toys' indestructibility: A single Lego could take hundreds of years to break down in the ocean.

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Alis Deason and her team have finally found the edge of the Milky Way galaxy!

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Questions or comments on this article? E-mail us at feedback@sciencenews.org | Reprints FAQ

A version of this article appears in the April 25, 2020 issue of Science News.

Ken Croswell has a Ph.D. in astronomy from Harvard University and is the author of eight books, including The Alchemy of the Heavens: Searching for Meaning in the Milky Way and The Lives of Stars.

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Astronomers have found the edge of the Milky Way at last

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Computer simulations and observations of nearby galaxies let astrophysicists put a firm number on the Milky Way's size.